Knockdown of BACE1-AS Nonprotein-Coding Transcript Modulates Beta-Amyloid-Related Hippocampal Neurogenes.
Background. Alzheimer's disease (AD) is a devastating neurological disorder and the main cause of dementia in the elderly population worldwide. Adult neurogenesis appears to be upregulated very early in AD pathogenesis in response to some specific aggregates of beta-amyloid (Aβ) peptides, exhausting...
| Published in: | International Journal of Alzheimer's Disease Vol. 2011; pp. 1 - 12 |
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| Main Authors: | , , , , , |
| Format: | pictorial research tables/charts Journal Article |
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Wiley-Blackwell
2011
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=71369791&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 71369791 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 20900252 902P jtl: International Journal of Alzheimer's Disease issn: 20900252 maglogo: N pubinfo: dt: 2011 vid: 2011 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 71369791 71369791 71369791 10.4061/2011/929042 71369791 ppf: 1 ppct: 11 formats: tig: atl: Knockdown of BACE1-AS Nonprotein-Coding Transcript Modulates Beta-Amyloid-Related Hippocampal Neurogenes. aug: au: Modarresi, Farzaneh Faghihi, Mohammad Ali Patel, Nikunj S. Sahagan, Barbara G. Wahlestedt, Claes Lopez-Toledano, Miguel A. affil: Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Avenue Miami, FL 33136, USA sug: subj: Hippocampus Physiology Proteins Metabolism Alzheimer's Disease Physiopathology Animal Studies Mice Models, Biological Reverse Transcriptase Polymerase Chain Reaction Blotting, Western Enzyme-Linked Immunosorbent Assay Immunohistochemistry ab: Background. Alzheimer's disease (AD) is a devastating neurological disorder and the main cause of dementia in the elderly population worldwide. Adult neurogenesis appears to be upregulated very early in AD pathogenesis in response to some specific aggregates of beta-amyloid (Aβ) peptides, exhausting the neuronal stem cell pools in the brain. Previously, we characterized a conserved nonprotein-coding antisense transcript for β-secretase-1 (BACE1), a critical enzyme in AD pathophysiology. We showed that the BACE1-antisense transcript (BACE1-AS) is markedly upregulated in brain samples from AD patients and promotes the stability of the (sense) BACE1 transcript. In the current paper, we examine the relationship between BACE1, BACE1-AS, adult neurogenesis markers, and amyloid plaque formation in amyloid precursor protein (APP) transgenic mice (Tg-19959) of various ages. Results. Consistent with previous publications in other APP overexpressing mouse models, we found adult neurogenesis markers to be noticeably upregulated in Tg-19959 mice very early in the development of the disease. Knockdown of either one of BACE1 or BACE1-AS transcripts by continuous infusion of locked nucleic acid- (LNA-) modified siRNAs into the third ventricle over the period of two weeks caused concordant downregulation of both transcripts in Tg-19959 mice. Downregulation of BACE1 mRNA was followed by reduction of BACE1 protein and insoluble Aβ. Modulation of BACE1 and BACE1-AS transcripts also altered oligomeric Aβ aggregation pattern, which was in turn associated with an increase in neurogenesis markers at the RNA and protein level. Conclusion. We found alterations in the RNA and protein concentrations of several adult neurogenesis markers, as well as non-protein-coding BACE1-AS transcripts, in parallel with the course of β-amyloid synthesis and aggregation in the brain of Tg15999 mice. In addition, by knocking down BACE1 or BACE1-AS (thereby reducing Aβ production and plaque deposition), we were able to modulate expression of these neurogenesis markers. Our findings suggest a distortion of adult neurogenesis that is associated with Aβ production very early in amyloid pathogenesis. We believe that these alterations, at the molecular level, could prove useful as novel therapeutic targets and/or as early biomarkers of AD. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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